Angiogenesis, the proliferation of new blood vessel growth, is involved in the manifestation or progress of various diseases, for example, various inflammatory diseases (rheumatism, psoriasis), diabetic retinopathy, and cancer.
Therefore, to inhibit angiogenesis is considered to contribute to the treatment and prevention of such diseases. In fact, several groups of researchers have so far searched for angiogenesis inhibitory substances. As examples, there may be mentioned the study by Taylor, et al., [S. Taylor, et al., Nature, 297:307 (1982)] on the applicability of protamine and the study of Folkman, et al. [M. J. Folkman, et al., Science, 221:719 (1983)] on the combined use of heparin and cortisone. Furthermore, patent applications have been filed alleging, for example, that ascorbic acid ethers and related compounds (Japanese Kokai Tokkyo Koho No. 58-131978) and the sulfated polysaccharide DS4152 (Japanese Kokai Tokkyo Koho No. 63-119500) show angiogenesis inhibitory activity.
One particular troubling angiogenesis-induced disease is tumor growth and metastasis. The ability of a tumor to metastasize depends on its ability to stimulate angiogenesis in at least two time-points in its growth; first, a tumor must be vascularized in order to enter circulation [L. Liotta, Cancer Res., 34:997-1004 (1976)]; second, once it reaches the secondary site, the tumor must stimulate angiogenesis in order to expand [M. J. Folkman, Origins of Human Cancer: A Comprehensive Review, Cold Spring Harbor Laboratory Press, pp. 803-812 (1991)]. Other angiogenesis-induced diseases which present a problem to the medical community include rheumatoid arthritis, psoriasis and ocular angiogenic diseases including diabetic retinopathy.
Another group of angiogenesis inhibitors are fumagillin and O-substituted fumagillol derivatives such as those described in EPO Publication No. 0325199A2 and EPO Publication No. 0357061A1. The latter EPO Publication discloses O-substituted fumagillol derivatives of the general Formula I: ##STR1## wherein R.sup.1 is a 2-methyl-1-propenyl or isobutyl group which may be substituted and R.sup.2 is (1) a substituted alkanoyl group, (2) a substituted aroyl group having at least one substituent selected from the group consisting of C.sub.2-6 alkyl, amino, halogen, hydroxyl, lower alkoxyl, cyano, carbamoyl and carboxyl, (3) an aromatic heterocyclic-carbonyl which may optionally be substituted, (4) a carbamoyl group, which may optionally be substituted, (5) an alkyl group, which may optionally be substituted, (6) a benzenesulfonyl group, which may optionally be substituted, (7) an alkylsulfonyl group, which may be optionally substituted, (8) a sulfamoyl group, which may optionally be substituted, (9) an alkoxycarbonyl group, which may optionally be substituted or (10) a phenoxycarbonyl group which may optionally be substituted, or salts thereof.
Other inhibitors of angiogenesis include the lymphokine interferon. For example, interferon .alpha./A or human interferon .beta. has been shown to inhibit tumor-induced angiogenesis in mouse dermis stimulated by human neoplastic cells. [Y. Sidky, et al., Cancer Research, 47:5155:5161 (1987)] Likewise, interferon .beta. is also a potent inhibitor of angiogenesis induced by allogeneic spleen cells. [Y. Sidky, et al., Cancer Research, supra] Human recombinant .alpha. interferon (.alpha.2A) was reported to be successfully used in the treatment of pulmonary hemangiomatosis, an angiogenesis-induced disease. [C. White, et al., New England J. Med., 320:1197-1200 (1989)] However, interferon has only been shown to exhibit a relatively minor angiogenesis inhibitory effect and thus, interferon is only mildly effective in the treatment of angiogenesis induced diseases.
Accordingly, it would be desirable to have agents or novel combinations of agents which improve the inhibition of angiogenesis and thus the treatment of angiogenesis-induced diseases.